Hepatitis C is a major health problem within the United States and the world. Recently, considerable progress was made in understanding the nature of this disease. Recently considerable progress was made by identifying CD81 as a putative ligand of the Hepatitis C virus. For the past several years, our laboratory has focused on the role of CD81 in the regulation of cell growth. The overall goal of the present proposal is to investigate the molecular associations of CD81 in the liver that may contribute to binding or entry of the hepatitis C virus. We hypothesize the CD81 is part of a molecular complex which varies between different body tissues. By defining components of this complex in the liver and comparing this to other tissues, we will begin to reveal specific molecular interactions critical to the virus interactions with CD81. The present proposal is designed to answer three questions related to hepatitis C infections. 1) What tissues and cells within the human body express CD81? 2) Is CD81 part of a molecular complex within the plane of t he membrane, and does the components of this complex change from tissue to tissue? 3) Is it possible to block or alter the interaction of hepatitis C with CD81 by altering cis interactions within the plane of the membrane or trans interactions with the E2 protein on the hepatitis C virus. This information will define the potential targets for Hepatitis C. By comparing the cells expressing CD81 and t he cells capable of the binding the virus, we will use subtractive methods to identify potential co- receptor molecules on the surface of the cell. This information can then be used to examine potential allelic variation in populations of patients that either spontaneously recover from hepatitis C infection or that are predestined to develop chronic infections. Once we identify genetic differences that result in alterations in alterations in the progression of hepatitis C infection or that are predest8ned to develop chronic infections. Once we identify genetic difference that result in alterations in the progression of hepatitis C infections, we may be able to develop treatment protocols to better treat this disease.